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Why neurons lose their spark?

It appears as a consequence of TDP-43 and FUS/TLS proteins getting in a bind outside the nucleus of our motor neurons and not returning to the nucleus, they miss out on manufacturing proteins essential for the continuing function of the motor neuron synapses. True in mice and human cell culture.

Excess TDP-43 is toxic to the function of our motor neurons.

The process that causes profilin 1 to clump together is always in the presence of misfolded TDP-43, but there are other processes that cause TDP-43 to misfold that do not affect profilin 1. It would therefore appear that misfolded TDP-43 is a downstream event of the clumping of profilin 1 or the synthesizing of faulty profilin 1 is linked inextricably with TDP-43.

Profilin 1 is a protein that constructs the motor neuron including the long axon projection that connects to other motor neurons or muscles.

Also note that the Super Oxide Dismutase(Destroyer) protein also misfolds in SOD1 variant MND. Misfolded proteins are always present at autopsy in MND sufferers.

Hi Graham,thanks for that,I thought that had to be the case,with research reports I've read they seem to have a problem with crossing the brain blood barrier.
In the past if I was to have a sherry it would go straight to my legs making them feel really heavy and ache,this would happen within 10 minutes so I would think another way to cross the BBB.Why I am harping on this is perhaps these readily available products could be used to piggy back whatever through the BBB.

The sherry will contain ethanol (alcohol) among other compounds. Ethanol will pass BBB and act as a GABA inhibitor in the Upper Motor Neurons causing spastic diplegia, the heavy feeling in your legs. This is an indicator that you have UMN involvement. Ethanol also impacts other brain functions.

Diseased motor neurons contain between 2-fold and 5-fold amounts of TDP-43 than their healthy counterparts.

The excess TDP-43 in the cytoplasm of the motor neuron that remains completely unprocessed is particularly toxic to the neuron. Partially processed TDP-43/mRNA is tolerated by the motor neuron. TDP-43 toxic motor neurons are marked for destruction.

The excess unprocessed TDP-43 is a highly charged protein and will unbalance the osmoregulation of the motor neuron.

The excess TDP-43 within the motor neuron will also cause "molecular crowding". Electrolytic concentration gradients within the motor neuron will be disturbed and will impact cellular processes within the motor neuron.

The physical presence of the excess TDP-43 means less space is available for other cells within the motor neuron. This will consequently impact cellular processes too.

One approach for therapy is to rid the motor neuron of excess TDP-43. 58000 compounds have been tested and over 2000 have been identified as being over 30% effective. Testing continues. Thanks Olly. However, merely clearing excess TDP-43 is not going to restore neuron function.

Motor neurons have 'little helpers' that clear tangled TDP-43 and other proteins marked as junk. They are called Proteasomes. The markers of junk protein are called ubiquitin.

There is a lot of molecular machinery in play and critical gene mutations results in poor quality machinery that cannot function. One such gene mutation makes faulty 'markers of junk', ubiquitin. The proteasome is not able to grapple the marker and feed the junk protein inside its barrel for recycling.

There are compounds that enhance the performance of the proteasome. One such compound is melittin, found in bee venom. A very interesting experiment carried out on SOD1 mice found that melittin did indeed enhance the function of the proteasome and the mice responded by being more active in life, but lifespan was unaffected.

We want TDP-43 not to misfold in the first instance, and maintain function in the motor neuron.

Is it possible to modify gene expression?

Yes. Phase 1 trials completed during 2012 in Washington USA proved the technique is safe in ALS patients. Called Anti-sense gene therapy, proteins are designed to interfere with motor neuron RNA and block faulty gene expression.
In June 2014 anti-sense gene therapy work started at Sheffield University, UK.

A special mention of repeat sequence bases must be made. It appears the inability of genes to count repeat sequence bbbbases when replicating or maybe viruses home in on these genetic sites when launching their attack.
Repeat base flaws come in varying lengths. The longer the repeat baaaase, the earlier the onset and more severe the consequences.

In June 2014 the 'Whole Genome Project' was launched in the UK. 100,000 participants will have their whole genome sequenced of which 1,500 will be drawn from the MND sufferer community.

When our lower motor neurons are stressed, the resident 'police' cells external to the motor neuron, called microglial cells, sense the stress. The microglial cells, otherwise named astrocytes, send out a message 'Call in the cavalry!'.

These messages exit the spinal cord and locate the 'response team', called monocytes, on patrol in the bloodstream. The messages are specifically coded, 'Motor Neurons in Distress'. For each message received, the monocytes create a battalion of monocytes with the CD14+/CD16- first responders, to rescue the motor neurons. The more distress messages received, more CD14+/CD16- first responders will be created. These are the inflammatory biomarkers for ALS.

The extent of stress the Lower Motor Neurons are suffering may be measured using the CD14+/CD16-biomarkers.

The M1 first responders on the scene at the motor neurons hunt for motor neuron cells displaying an 'eat me' tag. Damaged motor neurons are removed.

It is NP001, chlorite ions, that change the 'Battle Response' to M2, recovery phase prematurely, to save damaged neurons from being eaten.

An alternative approach being researched is to call off the cavalry by suppressing M1 monocytes. It must be appreciated that both these approaches do not affect the demise of the Lower Motor Neurons, it merely maintains better function of the Lower Motor Neurons during the diseased phase.

It has been found that the immune response in mice reflects that in humans.

Mice with the faulty SOD1 gene develop MND predictably. Mice without the SOD1 gene do not develop MND! It is "faulty" SOD1 gene that "faulty" SOD1 proteins are manufactured(synthesized) from that gives rise to MND.

Mice with knockout SOD1 gene experience an accelerated motor neuron decline, but not the catastrophy of MND.

In 2014 a human MND model of the SOD1 variant of the disease revealed faulty SOD1 proteins spreading from one neuron too others in the classic cascade pattern explaining the spread of symptoms that we are all familiar with.

Hi Graham, thanks for keeping us up to date with this, it is much appreciated. Hope the fun screws not too tight today, I did say some screws, I did say thumb screws. I am using the Dragon voice activated system, it must be the way I talk, anyway you take care regards Bob